Drugs can be administered parenterally as a depot formulation for the treatment of certain diseases. Besides classical dosage forms, such as oily suspensions, modern dosage forms on the basis of biocompatible/biodegradable polymers can be used. The implants (single-unit systems) or microparticles (multiparticulate systems) are prepared from the solid polymeric carriers and are then placed in the body by implantation or injection.
For the implant preparation, the drug is mixed with the carrier (e.g., a polymer) and is then processed into the desired implant shape (e.g., cylinder, pellet, film, fiber), for example by extrusion or compression at elevated temperatures. Such solid implants are then usually placed in the body by a surgical procedure or through hollow needles with a large diameter.
Drug-containing microparticles can be used in order to circumvent such surgical procedures with implants, which are highly undesired by patients. Suspensions of these particles can be injected with a syringe through an injection needle. These microparticles are prepared outside the body by various methods, such as for example the solvent evaporation, organic phase separation, or spray-drying techniques. In the solvent evaporation method, which is frequently used for the preparation of biodegradable microparticles, a drug is dissolved or dispersed in a solution of a biodegradable polymer (e.g., polylactic acid) in a solvent (e.g. methylene chloride), which is not miscible with water. This drug-containing polymer phase is then emulsified in an external aqueous phase and forms drug-containing polymer droplets. The microparticles are obtained after evaporation of the solvent through the solidification of the polymer and are then separated from the aqueous phase (e.g., by filtration) and dried.
Commercially available biodegradable microparticle products (e.g., Decapeptyl, Enantone) consist of a dry powder of the microparticles and an aqueous suspension vehicle. The microparticles and the aqueous suspension vehicle are stored separately, for example in multi-chamber (having two or more chambers) syringes or in two ampoules, because of the hydrolytic instability of the biodegradable polymers. The microparticles are then suspended in the aqueous suspension vehicle just prior to the administration and are then injected. The preparation of these biodegradable particle products is very elaborate and has to be done under sterile or aseptic conditions. In addition, most microencapsulation techniques are difficult or not at all transferable to the production size and are dependent on many process- and formulation variables. The suspension of the microparticles and the subsequent injection can also cause difficulties (e.g., agglomeration, residual microparticles in the syringe, clogging of the needle, etc.).
Aside from the water-insoluble polylactic acid derivatives and other water-insoluble polymers, hydrophilic polymers can also be used as carrier materials for microparticles and implants. Microparticles of hydrophilic polymers (e.g., polysaccharides, such as alginates or chitosan, cellulose derivatives, protein—(collagen) derivatives) can be prepared for example through spray-drying or w/o-emulsification techniques, whereby the drug-containing aqueous polymer solution is either spray-dried or emulsified into an external oil phase, whereby the particles are obtained after removal of the water, washing, filtration and drying. Like the techniques for the preparation of polylactic acid microparticles, the microencapsulation techniques with the hydrophilic polymers are also very elaborate.
U.S. Pat. No. 4,938,763 discloses a composition based on a drug-containing polymer solution. The composition was developed in an attempt to avoid problems with the preparation and administration of implants or microparticles. A solution of polylactic acid (or a derivative) is injected into the body, for example intramuscularly, subcutaneously, or periodontally and an implant is formed in-situ through the precipitation of the polymer in the tissue and the drug is then released slowly. The implant is therefore not formed outside, but inside the body. The drug is either dissolved or dispersed in the polymer solution, or in the case of stability problems, it is stored separately from the polymer solution. The preparation of this composition is much easier than the preparation of conventional implants or microparticles. A commercial product based on this in-situ implant technology (Atrigel-technology) is already available in the USA and is in the approval process in Europe. This product has the trade name ATRIDOX and is used for the periodontal administration of doxycycline. The drug doxycycline and the polymer solution (consisting of the polymer, poly(dl-lactide) dissolved in the solvent N-methyl-2-pyrrolidone) are separately stored in two syringes because of stability reasons. The drug and polymer solution are mixed shortly before administration through a connector, which connects both syringes, by forward-and-backward pushing of the syringe plungers and are then administered. A 200-times forward-and-backward pushing of the plungers is necessary in order to obtain a good distribution of the drug in the polymer solution prior to administration. It is important to note that the ATRIGEL system requires the preformation and storage of a polymer solution in a syringe. The polymer used is not a fast dissolution rate polymer nor is it a highly soluble polymer and thus requires large amounts of solvent in preparing the polymer solution. The polymer takes several hours and even up to a full day to dissolve.
Other systems have been developed, whereby a solidification/viscosity increase of drug-containing polymer solutions after administration/injection in the body was caused primarily by a temperature- or pH-change or by special substances (e.g., ions), and not by diffusion of the solvent. These systems have the same disadvantages as the systems described in the previous two paragraphs. The polymer solution has to be injectable through a needle, it therefore cannot be too viscous. The possible polymer content is therefore primarily limited by the viscosity of the polymer solution and not through the solubility of the polymer. In addition, precipitation of the polymer during the injection of the polymer solution can negatively influence the injection of the remaining polymer solution. Disadvantages of this method are also the use of high amounts of solvents having toxicity and compatibility problems and, after injection into soft tissue, the somewhat uncontrollable solidification of the polymer resulting in an undefined surface area of the implant. This can lead to irreproducible release profiles. In addition, the drug can be released rapidly prior to the solidification of the polymer solution. This so-called burst-effect is usually undesirable.
WO 98/55100 describes compositions, which are easy to prepare and which avoid problems obtained during the development and administration of microparticles and implants, including the described in-situ implants. These compositions form particles and/or implants after placement in the body and are obtained after mixing an inner polymer-containing carrier phase with an immiscible or partially immiscible second external phase, whereby the viscosity of the carrier phase is changed after a change in ambient conditions. For example, an active compound-containing dispersion, comprising an inner carrier phase and a second external phase (e.g., an oil) may be prepared and be placed into the body. The inner phase then solidifies, for example through solvent diffusion in the environment or diffusion of body fluids into the carrier phase, or through a change in temperature, pH-value or ionic strength. The carrier material is dissolved in a solvent and present as a solution in its packaging material. The carrier material is not present as a solid. For example, in the case of biodegradable polymers, the dispersion may be injected i.m. or s.c., in the case of peroral administration, the liquid dispersion can be filled into capsules. The inner phase can solidify in contact with body fluids and can form, for example, particles. The carrier phase can also be mixed with the second external phase just prior to administration. This can be required, if the dispersion is physically unstable, which means that the internal carrier phase separates from the second external phase.
U.S. Pat. No. 5,081,156 discloses an injectable composition that is an oily suspension of drug-collagen particles. The composition does not form an implant or particles although it is reconstituted prior to use. The carrier material does not harden after injection into a subject and the carrier material is not dissolved after reconstitution of the suspension.
U.S. Pat. No. 5,595,760 discloses an injectable composition wherein a peptide drug gels in a subject after injection of the composition into the subject. The carrier material used does not solidify and does not provide an extended release of drug as the longest release period achieved is about 3 hours. This patent does not disclose the formation of an implant or particles.
Aside from chemical stability, physical stability plays an important role with liquid dispersed systems, for example with drug suspensions in polymer solutions. During storage of prior art systems, sedimentation and the formation of a non-redispersible cake can occur.
Thus, none of the known art discloses a system for the formation of implants or particles in vivo wherein the implant or particles provides an extended release of drug, the carrier material is dissolved in a solvent just prior to use, the carrier material is present as a solid in a kit, and the carrier material hardens in a subject after injection.